The present invention is in the general area of polymers for biomedical application and in particular is a group of unsaturated polyanhydrides having a double bond available for secondary polymerization.
A number of polymers have been used in biomedical applications including polyanhydrides, polyorthoesters, polylactic acid, and polyvinylacetate. One of the advantages of polyanhydrides in these applications is that they are both biodegradeable and biocompatible.
One major application is in biodegradable controlled release systems. These devices obviate the need to surgically remove the drug-depleted device. Biodegradable matrix systems also enjoy a number of other advantages in terms of simplicity in design and predictability of release if the release is controlled solely by the degradation of the matrix. In many cases, however, the release is augmented by diffusion though the matrix, rendering the process difficult to control. This is particularly true if the matrix is hydrophilic and therefore absorbs water, promoting degradation within the interior of the matrix. To maximize control over the release process, it is desirable to have a polymeric system which degrades only from the surface and deters the permeation of the drug molecules. Achieving such a heterogeneous degradation requires the rate of hydrolytic degradation on the surface to be much faster than the rate of water penetration into the bulk. Accordingly, the ideal polymer has a hydrophobic backbone in combination with a water labile linkage.
Polyanhydrides were initially proposed by Hill and Carouthers in the 1930's to be a substitute for polyesters in textile applications. The idea was later rejected because of their hydrolytic instability. However, it is this property that renders polyanhydrides appealing for controlled-release applications.
Aromatic and aliphatic polyanhydrides were first synthesized in 1909 and 1932, respectively. The methods most commonly used were melt-polycondensation methods. (Yoda, et al., Bull. Chem. Soc. Jpn., 32, 1120 (1959)). The materials used in textile applications, while useful, can provoke an inflammatory response when used in vivo for medical applications. Further, their release characteristics are not always uniform.
Characterization of the degradation and release characteristics, and the biocompatibility and chemical reactivity, of polyanhydrides as drug-carrier matrices was reported by Leong, et al., in J. Biomed. Matter. Res., 19, 941-955 (1985) and 20, 51-64 (1986). The polyanhydrides used by Leong et al are vastly improved over the polyanhydrides first prepared for use in textiles. These studies indicate that the method for manufacture as well as the purity of the starting materials can be improved in order to improve the in vivo response, i.e., decrease the inflammatory response and improve linear release.
Co-pending application U.S. Ser. No. 892,809 filed Aug. 1, 1986 by Abraham J. Domb and Robert S. Langer entitled "Synthesis and Application of High Molecular Weight Polyanhydrides" discloses one approach to overcoming the deficiencies in both the mechanical and physical properties of the polymers as well as the in vivo response. Their method is to synthesize high molecular weight polyanhydrides from extremely pure diacids and isolated prepolymers under optimized reaction conditions. High molecular weight polyanhydrides were defined as having an intrinsic viscosity of greater than 0.3 dl/g in chloroform at 23.degree. C. and a weight average molecular weight of greater than 20,000.
It is important for drug-delivery applications to have polymers having good solubility, required for film casting or microencapsulation, as well as stability both in solution and in the solid state. Studies of the stability of polyanhydrides in solution and in solid state have demonstrated that linear polyanhydrides tend to depolymerize. Aromatic polyanhydrides are more stable but, unfortunately, also less soluble. If the linear polymers could be crosslinked after polymerization, their stability would not only be enhanced but new applications could be developed.
It is therefore an object of the present invention to provide cross-linkable polymers which are stable in solution yet which can be solubilized for film casting or microencapsulation.
It is another object of the present invention to provide soluble polymers having linear release when cast as controlled drug-delivery devices.
It is still another object of the present invention to provide polymers which can be cross-linked for use in biomedical applications such as in bone adhesion.